Association of IFNL3 and IFNL4 polymorphisms with liver-related mortality in a multiracial cohort of HIV/HCV-coinfected women.

African Americans coinfected with HIV and hepatitis C virus (HCV) have lower liver-related mortality than Caucasians and Hispanics. While genetic polymorphisms near the IFNL3 and IFNL4 genes explain a significant fraction of racial differences in several HCV-related outcomes, the impact of these variants on liver-related mortality has not been investigated. We conducted a cohort study of HIV/HCV-coinfected women followed in the multicentre, NIH-funded Women's Interagency HIV Study (WIHS) to investigate whether 10 polymorphisms spanning the IFN-λ region were associated with liver-related mortality by dominant, recessive or additive genetic models. We also considered whether these polymorphisms contributed to previously reported differences in liver-related death by race/ethnicity (ascertained by self-report and ancestry informative markers). Among 794 coinfected women, there were 471 deaths including 55 liver-related deaths during up to 18 years of follow-up. On adjusted analysis, rs12980275 GG genotype compared to AG+AA hazards ratios [(HR) 0.36, 95% CI 0.14-0.90, P = 0.029] and rs8109886 AA genotype compared to CC+AC (HR 0.67, 95% CI 0.45-0.99, P = 0.047) were most strongly associated with liver-related death although these associations were no longer significant after adjusting for race/ethnicity (HR 0.41, 95% CI 0.16-1.04, P = 0.060 and HR 0.78, 95% CI 0.51-1.19, P = 0.25, respectively). African American women had persistently lower liver-related death independent of IFN-λ variants (HRs ≤ 0.44, P values ≤ 0.04). The lower risk of death among African American HIV/HCV-coinfected women is not explained by genetic variation in the IFN-λ region suggesting, that other genetic, behavioural and/or environmental factors may contribute to racial/ethnic differences in liver-related mortality.

Risk alleles for chronic hepatitis B are associated with decreased mRNA expression of HLA-DPA1 and HLA-DPB1 in normal human liver.

A genome-wide association study identified single nucleotide polymorphisms (SNPs) rs3077 and rs9277535 located in the 3' untranslated regions of human leukocyte antigen (HLA) class II genes HLA-DPA1 and HLA-DPB1, respectively, as the independent variants most strongly associated with chronic hepatitis B. We examined whether these SNPs are associated with mRNA expression of HLA-DPA1 and HLA-DPB1. We identified gene expression-associated SNPs (eSNPs) in normal liver samples obtained from 651 individuals of European ancestry by integrating genotype (~650 000 SNPs) and gene expression (>39 000 transcripts) data from each sample. We used the Kruskal-Wallis test to determine associations between gene expression and genotype. To confirm findings, we measured allelic expression imbalance (AEI) of complementary DNA compared with DNA in liver specimens from subjects who were heterozygous for rs3077 and rs9277535. On a genome-wide basis, rs3077 was the SNP most strongly associated with HLA-DPA1 expression (p=10(-48)), and rs9277535 was strongly associated with HLA-DPB1 expression (p=10(-15)). Consistent with these gene expression associations, we observed AEI for both rs3077 (p=3.0 × 10(-7); 17 samples) and rs9277535 (p=0.001; 17 samples). We conclude that the variants previously associated with chronic hepatitis B are also strongly associated with mRNA expression of HLA-DPA1 and HLA-DPB1, suggesting that expression of these genes is important in control of HBV.

Expression analysis of loci associated with type 2 diabetes in human tissues.

AIMS/HYPOTHESIS: Genetic mapping has identified over 20 loci contributing to genetic risk of type 2 diabetes. The next step is to identify the genes and mechanisms regulating the contributions of genetic risk to disease. The goal of this study was to evaluate the effect of age, height, weight and risk alleles on expression of candidate genes in diabetes-associated regions in three relevant human tissues. METHODS: We measured transcript abundance for WFS1, KCNJ11, TCF2 (also known as HNF1B), PPARG, HHEX, IDE, CDKAL1, CDKN2A, CDKN2B, IGF2BP2, SLC30A8 and TCF7L2 by quantitative RT-PCR in human pancreas (n = 50), colon (n = 195) and liver (n = 50). Tissue samples were genotyped for single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. The effects of age, height, weight, tissue and SNP on RNA expression were tested by linear modelling. RESULTS: Expression of all genes exhibited tissue bias. Immunohistochemistry confirmed the findings for HHEX, IDE and SLC30A8, which showed strongest tissue-specific mRNA expression bias. Neither age, height nor weight were associated with gene expression. We found no evidence that type 2 diabetes-associated SNPs affect neighbouring gene expression (cis-expression quantitative trait loci) in colon, pancreas and liver. CONCLUSIONS/INTERPRETATION: This study provides new evidence that tissue-type, but not age, height, weight or SNPs in or near candidate genes associated with increased risk of type 2 diabetes are strong contributors to differential gene expression in the genes and tissues examined.

Evidence for neuroendocrine function of a unique splicing form of TCF7L2 in human brain, islets and gut.

AIMS/HYPOTHESIS: Variants in the TCF7L2 gene remain the strongest genetic associations with increased risk of type 2 diabetes. Recently, we identified a unique splicing form of TCF7L2 expressed in pancreatic islets, pancreas and colon and detected by assay 'ex13-13b'. The expression of ex13-13b strongly correlated with proinsulin in glucose-stimulated pancreatic islets, suggesting a potential role for this form in the development of type 2 diabetes. The goal of this study was to further characterise this unique TCF7L2 splicing form in human tissues. METHODS: We used a panel of 34 human tissues and 80 human cell lines to measure the expression of assay ex13-13b with use of quantitative RT-PCR. RESULTS: The highest expression of assay ex13-13b was detected in several areas of the brain (hypothalamus/thalamus, occipital lobe) and in neuronal cell line SHS5Y5. Low expression was confirmed in pancreatic islets, small intestine, pancreas and colon, while no expression was detected in other human tissues and cell lines. The expression of assay ex13-13b correlated with the gene for cocaine- and amphetamine-regulated transcript (CART, also known as CARTPT) in a panel of human tissues (n = 12, r = 0.85, p = 0.00046), pancreatic islets (n = 23, r = 0.62, p = 0.0016) and colon (n = 98, r = 0.54, p < 0.0001). CONCLUSIONS/INTERPRETATION: The significant correlation between expression of a unique splicing form of TCF7L2, named here TCF7L2-NE, and CART, the gene for an anorexigenic neurohormone expressed in the central and peripheral nervous system, suggests that these transcripts may share neuroendocrine functions important for brain, gut and pancreatic islets.

Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort.

We evaluated the roles of five single-nucleotide polymorphisms (SNPs) within PDCD1, and haplotypes defined by these SNPs, for the development of systemic lupus erythematosus (SLE) and specific sub-phenotypes (nephritis, antiphospholipid antibody positive, arthritis and double-stranded DNA positive) within a multiethnic US cohort of 1036 patients. Family based analyses were performed using 844 simplex families from four ethnic groups (Caucasian, Asian, Hispanic and African American). Subjects were genotyped for five 'tag' SNPs (selected from 15) to provide complete genetic information in all main ethnic groups. We employed transmission disequilibrium testing to assess risk for SLE by allele or haplotype, and multiple logistic regression analysis of SLE cases to examine associations with specific sub-phenotypes. In family based analyses, a haplotype containing the PD1.3A allele was significantly associated with SLE susceptibility among Caucasian families (P=0.01). Among Hispanic families, two novel SNPs were associated with SLE risk (P=0.005 and 0.01). In multivariate logistic regression analyses, five haplotypes were associated with specific sub-phenotypes among the different ethnic groups. These results suggest that PDCD1 genetic variation influences the risk and expression of SLE and that these associations vary according to ethnic background.